Preparation of n-acyl sulfanilamide



l atented Nov. 16, 1948 PREPARATION OF N -ACYL SULFANILAMI DE William B. Tarpley, J r., Chatham, N. J and August I. Ryer, New York, N. Y., assignors to Schering Corporation, Bloomfield, N. J a corporation of New Jersey No Drawing.

8 Claims.

ing agents usually produces only the N -acyl derivative, or, in a greatly preponderating proportion at higher temperatures, the N N -diacyl derivatives are produced. 1

The only commercial method for the manufacture of the N -acyl sulfanilamides, a num ber of which have been found to be important therapeutic agents, has been by a multi-step process (Crossley Northey-8z Hultquist'J. A. C. S. 61, 2950-5, 1939; and K. A. Jensen and F. Lundquist, Dansk Tidsskrift for Farmici 14, 129-33, 1940) but the yields have-beenrather low. The most widely used method hasflbeen to treat an N=-acyl sulfanilamide with an acylating agent, such as an acylanhydride or an acyl chloride. The thus-formed N N' -diacyl compound is then subjected to 'a partial. hydrolysis whereby the N -acyl group is split off, yielding the 'N -acy1 sulfanilamide. This 1 last step. is mainly responsible for; the low yield of the desired N acyl compound, for the hydrolysis of the acyl compound yields also the completely deaoylated, product,-namely 'sulfanilamide, while some of the diacyl compound remain unreacted. The further purification of themixture involves additional expense and further reduction in the yield. Low yields are obtained "even when the N -acyl group is one which splits ofi more readily on hydrolysis than the N -group. Where the N -acyl group isone which is relatively easy to ,hydrolyze, further difficulties are encountered in 'the known procedure in the attempt'to obtain a satisfactory yield.

It :will be recognizedthat in theknown procedure where different acyl groups-are to be attachdutfl the N and'N a two step acylation process is required." In addition, it is important in the known procedures to attach tothe N -atom an acyl groupwhich' is in allcase's more readily hydrolyzable than the N -acyl group, regardless Application December 10, 1943, Serial No. 513,716

of how easily hydrolyzable the lattermay be. Also, no matter how easily hydrolyzable the N -acy1 group maybe, the hydrolysis step must usually be so vigorous that a considerable amount of hydrolysis takes place also at the N group.

According to the present invention the N mono-acylation of "the sulfanilamide, and substantially exclusively atthe N -position, is accomplished in a single step, and an intermediate mono-acylatedproduct is obtained which is easily converted to l the N -acyl sulfanilamide with practically no danger of hydrolysis at the N -group. l r

We have found ,that N -acyl sulfanilamides, non-acylated at the N -position, can be prepared in much higher yields than formerly and in a single acylationostep', without theunecessity for any vigorous subsequent hydrolysis, and by starting with the readily obtainable parent compound, sulfanilamide.'- The present invention is based upon our discovery that the p-amino group can be bound by a strongacid and thereby rendered inactive toward the acylating agent employed for making the N -acyl derivative. Thereby a salt or acid addition product is formed, the N becoming pentavalent and non-substitutable. Among the strong-acids that can beemployed in our process are perchloric, 'chlorsulfonlc and sulfuric acids. 1 i

By the expression strong acid as employed in .this specification and in the appended claims is to ,be understood those. acids which are capable offoiming acid addition products with the pamino group "of sulfanilamide unde approximately anhydrous conditions. r

,In carrying out our invention, sulfanilamide is dissolved or suspended in anappropriate s01- vvent which contains or has added thereto a sufficient amount of a strong mineral or inorganic acid to bind the p-amino group; there is then added a sufficient amount of an acylating agent to react not only with the sulfanilamide but also with any water present in the system, the reaction preferably taking place under as anhydrous conditions as possible. ,Theireaction proceeds quite rapidly when. carried out at substantially room temperature. 7 If a-minimum of solvent has been used the inorganic acid salt of the N -acyl sulfanilamide. precipitates] out of the reaction "mixture; The precipitate is collected by filtration and is dissolved in water or alkali to remove the combininginorganic acid, whereupon the N -acyl sulfanilamide is precipitated from this solution by adjusting the pH, for example to a value of 4.

By our improved process, the binding of the p-amino group and the acylation at the N -position take place concurrently, that is, in a single step; while the splitting oif of the acid group from the N -position is effected by a relatively mild treatment which has practically no effect on the N -acyl; group. As a result, much'higher yields of the N -acyl derivative are obtained than heretofore and the product can be much more easily separated in pure condition than by the known processes.

Our invention will be described in greater detail in the following examples which are presented for purposes of illustration and not as indicating the limits of the invention.

Example 1 17.2 grams of sulfanilamide are dissolvediin 260 cc. of approximately 0.6 molar perchloric acid in acetic acid (prepared by mixing 90 g. of 70-72% perchloric acid with 190 g. acetic anhydride-and diluting to 1 "liter with glacial acetic acid),'-an'd 15 cc. of acetic anhydride are added.

The mixture isstirredfor one hour, allowing it to-come to room temperature, and then filtered with suction. The moist-precipitate is dissolved in' sodium hydroxide, the solution treated withdecolorizing charcoal at room temperature, and filtered. The pH of the filtrate is' adjusted to 4 with concentrated hydrochloric acid. and stirred for one-half hour at 10 C. The precipitatecl N -acetyl sulfanilamide is filtered and dried. Yield of crude N -acetyl sulfanilamide is 19.5 grams (92% of theory).

Example 2 17.2 .gramsof sulfanilamide aredissolved in 275 cc. glacial acetic acid bywarmingto 56 C.

18 grams of .70 72% perchloric acid are added and then 55 cc. acetic anhydride are run in, keep- .ing thetem'perature of the mixture below 50 C.

The-:Inixture'isstirr-ed for onehour. The precipitate isffiltered andthe wetfilter cakedissolved-in 15 cc. of-water and 7500. sodium hydroxide. The solutionis treated with decolorizing. charcoal, theifiltrate adjusted to "pH 4 with concentrated hydrochloric acid, and the mixture stirredfor one-half hour-at 10 'C. The

precipitate. is .filtered and dried. Yield of crude N -acetyl sulfanilamide is 17.5 grams (82% of theory). l

.Enaample 3 17.2 grams of sulfanilamide are suspended in '92 cc. glacial acetic acid, and 15.1 grams chlor- Example 4 17.2 grams of sulfanilamide'are suspended in 200cc. glacialacetic acid and l5 g. of chlor- Example 5 8.6 grams of sulfanilamide are stirred with 50 cc. of a solution of perchloric acid in propionic acid (prepared by mixing 71 g. of 70-72% perchloric acid with g. propionic anhydride) and 12 cc. of propionic anhydride are added. The

mixture is-stirred for one-half hour, cooled to room temperature-and the precipitate filtered. The precipitate is dissolved in water, the solution treated with decolorizing charcoal, and filtered. The filtrate is adjusted to pH 3 and chilled. The precipitated N -propionyl sulfanilamide is collected .by filtration and dried. Yield 7.0 g. (62% of theory).

The butyrate, valerate, isovalerate and benzoate can he prepared in the ways above described,

and it will be evidentthat also other acyl derivatives can be manufacture by the use of the corresponding anhydride or halide. In general,

no acid should be employed which will oxidize the sulfanilamide under the conditions of the reaction. Sulfuric acid, although it is an oxidizing agent in certain processes, does not act oxidizingly in the process above described.

As will be apparent from the'foregoing, the N -salts or addition products of the N -acyl sulfanilamides are difficultly soluble in the solvents-that are suitably employed in our process; they accordingly crystallize out during the course of the reaction and so can be eificiently isolated.

We claimt 1. Process for -the manufacture of 'N -a'cyl sulfanilamides which comprises treating sulfanilamide in an approximately anhydrous solvent with a strong mineral acid of the class consisting of perchloric, chlorsulfonic and sulfuric acids, to form an acid addition product at the p-amino group and subjecting the compound to the action of an acylating agent to form the N acyl derivative.

2. Process for the manufacture of N -acyl sulfanilamide which comprises treating sulfanilamide in'an approximately anhydrous solvent sulfanilarnide which comprises treating sulfanilamide in an approximately anhydrous solvent with chlorsul'fonicracid to form the acid addition product atzthe p-amino group and subjecting the'compound to theaction of an acylating agentto'formthe mono-acyl derivative, the acyl group being at the N -position.

4. Process for the manufacture of N -acyl sulfanilamides which comprises forming an acid addition product at the p-amino group of sulfanilamide with a strong inorganic acid in an approximately anhydrous solvent, said acid beinga member of the class consisting of perchloric, chlorsulfonic and sulfuric acids, reacting the product withan acylating agent to formthe N acyl derivative, and thereafter removing the mineral acid from the N -position by treatment with an inorganic base.

5. Process according to claim 1, wherein the acylating agent is an acetylatin compound.

6. Process according to claim 1, wherein the acylating agent is a propionlyating compound.

7. Process according to claim 1, wherein the reaction is conducted in glacial acetic acid solution at temperatures below 50 C.

8. Process for the manufacture of N -acy1 sulfanilamides which comprises treating sulfanilamide in an approximately anhydrous solvent with a strong mineral acid of the class consisting of per-chloric, chlorsulfonic and sulfuric acids to bind the p-amino group while simultaneously reacting the compound with an acylating agent to form the N -acyl derivative, dissolv- 6 ing the reaction product in aqueous sodium hydroxide solution, filtering the solution, adjusting the pH value of the filtrate to about 4, and separating the precipitated N -acyl sulfanilamide. 

